Cyclodextrins are cyclic compounds consisting of glucopyranose units through α-1,4-glycosidic linkages. The exterior surface of the cyclodextrin ring is hydrophilic, whereas the inside cavity thereof exhibits a hydrophobic character. Therefore, it is possible that other molecules referred to as “guest molecule” or part thereof, which are less polar than water (hydrophobic molecules) and have suitable dimensions to be required to fit into the cyclodextrin cavity, are included in the hydrophobic cavity of the cyclodextrin molecule and form inclusion compounds. The pharmaceutical applications with cyclodextrins are disclosed in many articles (Journal of Parenteral Science & Technology 43 (5), pp 231-240 (1989) and Pharmaceutical Research 14 (5), pp 556-567 (1997)).
Cyclodextrins consisting of 6, 7 or 8 glucopyranose units are generally referred to as α-, β- and γ-cyclodextrin, respectively. Although β-cyclodextrin is the most useful one of the above natural cyclodextrins for pharmaceutical preparations in terms of inclusion capacity and economical efficiency, it is not always ideal for drug formulations due to its relatively low aqueous solubility (1.8 g per 100 ml of water), serious renal toxicity and biological membrane incompatibility after parenteral administration. Therefore, its application is limited to merely food products or oral pharmaceutical preparations.
Recently, a number of chemically modified cyclodextrins such as alkylated-, hydroxyalkylated-, carboxyethylated- and sulfoalkylether-cyclodextrins have been prepared to improve the inclusion capacity and physicochemical properties of natural cyclodextrins.
Among them, as hydroxyalkylated group, Clue alkyl group is preferable, and hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl group can be enumerated. In particular, hydroxypropyl group is preferable. In addition, as sulfoalkylated group, C1-6 allyl group is preferred, and sulfomethyl, sulfoethyl, sulfopropyl and sulfobutyl group can be enumerated. In particular, sulfobutyl group is preferable. The specific product in the hydroxyalkylated cyclodextrins includes 2-hydroxypropyl-β-cyclodextrin, and the specific product in the sulfoalkylether cyclodextrins includes sulfobutylether-7-β-cyclodextrin Hydroxypropyl-β-cyclodextrin and sulfobutylether-7-β-cyclodextrin are especially suitable for the parenteral application because of their high water-solubility and minimal-toxicity, which are well disclosed in Journal of Pharmaceutical Science 85 (11), pp 1142-1169 (1996).
Further, with regard to cyclodextrin inclusion compounds, U.S. Pat. No. 4,371,673 discloses two types of water-soluble cyclodextrin complexes with retinoid-polymers and complexes of retinoids with ether type derivatives of cyclodextrins. U.S. Pat. No. 4,596,795 discloses results for administering a complex of sex hormone and cyclodextrin derivative via sublingual and buccal route. And U.S. Pat. No. 4,727,064 describes results on the conversion methods of drugs with ready crystallization and low water-solubility into intrinsically amorphous complexes, which have improved pharmaceutical properties by using cyclodextrin derivatives. U.S. Pat. No. 5,134,127 discloses sulfoalkylether cyclodextrin derivatives and their use as solubilizing agents for poorly water-soluble drugs for oral, intranasal or parenteral administration.
Recently, it has been proposed as a promising concept that solid tumor growth beyond a certain size requires newly-formed blood vessels for the transport of nutrients and oxygen, which is called to be angiogenesis-dependent, and it is expected that the inhibition of angiogenesis would provide a powerful and selective therapy for a wide variety of tumors. In particular, fumagillol derivative has been reported to exhibit pharmacological properties as an effective inhibiting agent for tumor-induced neovascularization by European Patent No. 415,294 and U.S. Pat. No. 6,063,812. However, further development of those compounds applicable to the clinical use is hampered considerably by the fact that they are poorly soluble in water and very unstable at room temperature.
It is well known that low drug solubility causes low absorption upon oral administration, precluding parenteral formulations. Furthermore, low stability imposes short shelf-life of products, low-temperature storage requirement and restrictions on mechanical movement, resulting in economical inefficiency and inconvenience.
Preparation studies of fumagillol derivatives are disclosed in several literatures. Solubility improvement of fumagillol derivatives was established in U.S. Pat. No. 5,196,406, but the stabilization of resulting products was not disclosed in the art. Other solubility improvement of fumagillol derivatives was established in European patent No. 519,428 but organic solvents such as ethanol, acetonitrile, isopropyl alcohol and acetone rather than cyclodextrins contributed more to the improved solubility. However, the use of organic solvent potentially may cause the side effects of the therapy. That is, further dilution in a large volume parenteral fluid such as saline or 5% dextrose solution on intravenous or intramuscular administration could lead to life-threatening precipitation followed by phlebitis due to the limited solubility. Also, in the art, stability was not consistent depending on the particular kind of cyclodextrin derivative. The stability of the mixture with maltosyl-β-cyclodextrin was improved, whereas the stability of the mixture with hydroxypropyl-β-cyclodextrin was rather worse than the parent compound alone. In addition, though the formulation with maltosyl-β-cyclodextrin seemed to be stable, maltosyl-β-cyclodextrin has not been yet guaranteed for a parenteral use, and its cost has made its universal use for various formulations economically unfavorable in contrast to hydroxypropyl-β-cyclodextrin that proved to be safe and economical. Also, though a stable composition of fumagillol derivatives was disclosed in U.S. Pat. No. 5,422,363, all excipients, fatty acid esters of glycerin or polyglycerin, used in the formulations are not suitable for the parenteral application.
Therefore, there was a need to convert fumagillol derivatives into a form, which is better soluble and stable, and thus possesses improved pharmaceutical properties.
Concerning the above, the inventors of the present invention developed novel fumagillol derivative and filed (U.S. Pat. No. 6,063,812), and the compounds used in the present invention are identical to the compounds disclosed therein.
The present inventors continued studies to provide fumagillol derivative preparations that can be applicable to parenteral administration such as intravenous or intramuscular injection, or oral administration by ensuring homogeneity, safety, bioavailability and stability under storage at room temperature through increasing solubility of fumagillol derivatives or their salts which were found to be superior as an angiogenesis inhibitor but unstable under storage at room temperature or in aqueous solution. As a result, we discovered that the inclusion compound of fumagillol derivative or its salt with hydroxypropyl-β-cyclodextrin or sulfobutylether-7-β-cyclodextrin is useful as an antitumor agent or antimetastatic agent with superior water-solubility and stability but low irritancy effect, and based on these, completed the present invention.
Therefore, the object of the present invention is to provide inclusion compound of fumagillol derivative or its salt with hydroxypropyl-β-cyclodextrin or sulfobutylether-7-β-cyclodextrin, and pharmaceutical composition comprising the same.